Biodiesels, fatty acid esters (FAEs), can be synthesized by condensation of fatty acid acyl CoAs and alcohols via a wax ester synthase in living cells. Biodiesels have advantageous characteristics over petrodiesels such as biodegradability, a higher flash point, and less emission. Controlling fatty acid and alcohol moieties are critical to produce designer biodiesels with desirable physiochemical properties (e.g., high cetane number, low kinematic viscosity, high oxidative stability, and low cloud point). Here, we developed a flexible framework to engineer Escherichia coli cell factories to synthesize designer biodiesels directly from fermentable sugars. In this framework, we designed each FAE pathway as a biodiesel exchangeable production module consisting of acyl CoA, alcohol, and wax ester synthase submodules. By inserting the FAE modules in an engineered E. coli modular chassis cell, we generated E. coli cell factories to produce targeted biodiesels (e.g., fatty acid ethyl (FAEE) and isobutyl (FAIbE) esters) with tunable and controllable short-chain alcohol moieties. The engineered E. coli chassis carrying the FAIbE production module produced 54mg/L FAIbEs with high specificity, accounting for>90% of the total synthesized FAEs and ∼4.7 fold increase in FAIbE production compared to the wildtype. Fed-batch cultures further improved FAIbE production up to 165mg/L. By mixing ethanol and isobutanol submodules, we demonstrated controllable production of mixed FAEEs and FAIbEs. We envision the developed framework offers a flexible, alternative route to engineer designer biodiesels with tunable and controllable properties using biomass-derived fermentable sugars.
Introduction: Natriuretic peptides (NP) are routinely used for the diagnosis of heart failure. Studies have suggested higher levels of NP in patients with cancer, possibly driven by cancer associated inflammation. This study aims to assess the performance characteristics of natriuretic peptides in predicting invasively measured elevated intracardiac filling pressures in patients with cancer. Methods: Patients with cancer who underwent a right heart catheterization (RHC) at a tertiary cancer center from 10/2011 to 10/2021 were identified. Demographic characteristics, NP levels and invasive hemodynamic data were abstracted. Pulmonary capillary wedge pressure (PCWP) > 15 mmHg and mean right atrial pressure (mRAP) > 8 mmHg were defined as abnormal. Results: Of 1240 patients who underwent a RHC, 740 had NTproBNP (41%) or BNP levels (23%) available within a median of 1 day (0-3, and 0-4 days, respectively) from the procedure. Of those, 46% were female, 70% were white, median age was 67 years (IQR: 58-74) and median BMI was 25.2 kg/m 2 (17.4-30.3). High PCWP was present in 58% of patients while an additional 15% had high mRAP with normal PCWP (73%). The area under the curve (AUC) of NTproBNP and BNP in predicting high PCWP was 0.626 (95% CI 0.578-0.675) and 0.681 (0.617-0.744), respectively. The AUC of NTproBNP and BNP in predicting high PCWP or high mRAP was 0.603 (0.549-0.657) and 0.690 (0.621-0.759), respectively. At 125 pg/ml, NTproBNP had a sensitivity of 95%, specificity 6%, positive predictive value (PPV) 57%, and negative predictive value (NPV) 48% for high PCWP and a sensitivity of 95%, specificity 9%, PPV of 74%, and NPV 41% for high PCWP or high mRAP. At 100 pg/ml, BNP had a sensitivity of 89%, specificity 25%, PPV 64%, and NPV 60% for high PCWP, and a sensitivity of 88%, specificity 28%, PPV 77%, and NPV 47% for high PCWP or high mRAP. Conclusions: NP at the standard cutoff levels are very sensitive in predicting elevated intracardiac filling pressures in patients with cancer. However, they can be falsely elevated in >70% of cancer patients with normal filling pressures. These caveats need to be considered when utilizing elevated levels of NP in the assessment of patients with cancer and dyspnea and/or edema.
Introduction: Atrial fibrillation (AF) is common in cardiac amyloidosis and often symptomatic. Commonly used therapeutics may be poorly tolerated. Patients with cardiac AL amyloidosis carry a high risk of stroke and bleeding, making anticoagulation challenging. This study examined the incidence of AF, treatment patterns, and incidence of thrombotic or bleeding complications. Methods: Patients with endomyocardial biopsy-proven cardiac AL amyloidosis treated at a tertiary cancer center between 6/2011 and 6/2020 were identified. Demographic and clinical data were abstracted. Outcomes included the development of AF, stroke and bleeding. Severe bleeding was defined as intracranial bleeding, hemorrhagic pericardial tamponade, or bleeding requiring endoscopic investigation. Results: Out of 43 patients with cardiac AL amyloidosis, 51% were diagnosed with AF during the follow up period (median 4.2 years (95% CI, 2.8-8.6)). Of those, 41% were women and 73% were white. Median age was 65.5 years (61-70). No significant demographic differences were identified between patients with and without AF. Beta-blockers were initiated in 86% and continued for more than 3 months in 59% of patients. Amiodarone was initiated in 50% and continued for more than 3 months in 18%. Treatment with digoxin and diltiazem were less common (27% and 14%, respectively). Pulmonary vein isolation was performed in 14% of patients. Anticoagulation (AC) was used in 59% of patients with AF and 19% of patients without AF for a different indication. Bleeding was common; 23% of AF patients reported an episode of severe bleeding, 60% of whom were on AC, in comparison to 19% in patients without AF, 50% of whom were on AC. Stroke was diagnosed in 14% of patients with AF, 67% of whom received AC, compared to 14% of patients without AF, 33% of whom received AC. Conclusions: Although AF is common (51%) in patients with cardiac AL amyloidosis, treatment with rate or rhythm control strategies is challenging. Many patients do not tolerate treatment for more than 3 months. While a significant number did not receive AC, there was a substantial risk of severe bleeding (1/4) and stroke (1/7). Given improved survival with newer therapies for AL amyloidosis, a greater focus on improving management of AF and outcomes is needed.
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